The application of the conditioning regimen of total lymphoid irradiation (TLl) and anti-thymocyte globulin (ATG) to leukemia and lymphoma patients undergoing hematopoietic cell transplantation (HCT) at the Stanford Medical Center has resulted in extension of the transplant procedure to the elderiy, and a very low incidence of acute graft versus host disease (GVHD) and transplant related mortality. However, the incidence of tumor relapse during the first 3 years after transplantation was about 50%. The patients with mixed chimerism had a relapse rate that was significantly higher than those with complete chimerism. The goals of the research program are to further study two new approaches for prevention and/or treatment of tumor relapse after HCT in mice that can be applied to clinical trials. In the first approach, we found that a subset of freshly isolated CD8+ memory T cells has potent graft anti-tumor (GVT) activity without inducing GVHD. The infusion of the latter cells into mixed chimeric mice with lymphoma relapse after transplantation resulted in conversion to complete chimerism and tumor cures after conditioning with conventional total body irradiation (TBI). We will determine whether this approach can be used in combination with the safer TLl based conditioning in mouse strain combinations that are MHC matched and mismatched, and study the molecular and cellular basis of tumor cures. We will apply the same approach in Phase l/ll clinical trials of patients with lymphoma relapse or at high risk for relapse due to mixed chimerism. In the second approach we will combine immunotherapy and allogeneic HCT for the prevention and treatment of lymphoma relapse by immunizing the donors to the idiotype protein tumor antigen. Our preliminary studies showed that the combination results in a marked increase in GVT activity. We will study the ability of infused CD8+ memory T cells from immunized donors to cure lymphoma relapse, and the molecular basis of enhanced GVT activity In both murine and human studies, recipients will be monitored for tumor burden, severity of GVHD, levels of chimerism and persistence of donor cells and CD8+ memory T cell clones.